Neuromuscular diseases associated with COVID-19 vaccines: a systematic review and pooled analysis of 258 patients

Background Neuromuscular diseases (NMD) emerged as one of the main side effects of the COVID-19 vaccination. We pooled and summarized the evidence on the clinical features and outcomes of NMD associated with COVID-19 vaccination. Methods We comprehensively searched three databases, Medline, Embase, and Scopus, using the key terms covering “Neuromuscular disease” AND “COVID-19 vaccine”, and pooled the individual patient data extracted from the included studies. Results A total of 258 NMD cases following COVID-19 have been reported globally, of which 171 cases were Guillain-Barré syndrome (GBS), 40 Parsonage-Turner syndrome (PTS), 22 Myasthenia Gravis (MG), 19 facial nerve palsy (FNP), 5 single fiber neuropathy, and 1 Tolosa-Hunt syndrome. All (100%) SFN patients and 58% of FNP patients were female; in the remaining NMDs, patients were predominantly male, including MG (82%), GBS (63%), and PTS (62.5%). The median time from vaccine to symptom was less than 2 weeks in all groups. Symptoms mainly appeared following the first dose of vector vaccine, but there was no specific pattern for mRNA-based. Conclusion COVID-19 vaccines might induce some NMDs, mainly in adults. The age distribution and gender characteristics of affected patients may differ based on the NMD type. About two-thirds of the cases probably occur less than 2 weeks after vaccination. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-023-03486-y.


Introduction
In the long term, vaccination remains vital in the COVID-19 pandemic control strategy [1].More than 13.3 billion COVID-19 vaccines have been administered globally; however, the fading of immunity over time necessitates booster doses; hence, about 1 million shots are still administered daily worldwide [2].
However, the extraordinary speed of vaccine production and the waiver of essential testing steps raised hesitancy regarding the vaccines' safety [3][4][5].A wide range of side effects are reported worldwide shortly after vaccination.While most side effects of vaccines are mild, their impact on the central and peripheral nervous systems often necessitates medical interventions [6][7][8][9][10].
Recently, increasing case series/reports have characterized the clinical course in patients with some types of peripheral neuropathy (Guillain-Barré syndrome, Parsonage-Turner syndrome, Small fiber neuropathy, and Tolosa-Hunt syndrome), cranial neuropathy (Facial nerve palsy), and neuromuscular junction disorder (Myasthenia gravis) [11] following COVID-19 vaccination.In this study, we pooled and summarized available evidence to enhance the knowledge of the course and prognosis of the neuromuscular diseases associated with COVID-19 vaccines, which can lead to a well-timed diagnosis and management of these patients.

Method
We conducted this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Patient consent or ethical approval was not required due to the review nature of the study.All studies reporting the symptoms and clinical course of patients with neuromuscular disease (NMD) associated with the COVID-19 vaccine were included.

Search
We comprehensively searched three databases, Scopus, Medline, and Embase, on 25 January 2023 and updated on 20 February 2023, using a combination of the key terms in multiple domains, including "COVID-19 vaccine", "Peripheral neuropathies", "Cranial neuropathy", "neuromuscular disease".Also, we checked the reference lists and citing publications of the included articles for any additional eligible studies.We imported all retrieved citations into Zotero 6.0.20 and removed the duplicate items.

Inclusion process and criteria
Two researchers [AT and PS] independently screened the titles, abstracts, and full texts of the studies to include the eligible articles.All studies meeting our eligibility criteria were included: 1. Reporting new-onset case (s) of any NMD following COVID-19 vaccination 2.An observational design: case series, case reports, and cohort studies 3. Written in English

Data extraction
Three researchers [EJ, SM, NM] extracted the data from the retrieved articles into a predefined form in Microsoft Excel (version 2019, Microsoft Corp., Redmond, WA, USA).The extracted data included the first author's name, year, country, age, gender, clinical data, type of the NMD, subtype of the disease, vaccine type, vaccine dose number (first, second, booster), the time between injection and symptom onset, presenting signs and symptoms, electrophysiological findings, laboratory data, treatment, and patients follow up.

Quality assessment
The quality of the included case series was assessed independently by two trained researchers (AA and SM) using the Joanna Briggs Institute (JBI) appraisal tool adapted for case series [12]; a third researcher (AT or HR) resolved any disagreement.JBI appraisal tool included 10 items, each receiving one score (Supplementary Table 1).

Statistical analyses
To organize the extracted individual patient data (IPD) and to produce tables, we used Microsoft Excel (version 2019, Microsoft Corp., Redmond, WA, USA).Based on the disease, we categorized integrated IPD case series and case reports into a relevant case series.After excluding cases without data for the characteristic of interest, we calculated a valid percent for each categorical and a median (Interquartile range) or mean and standard deviation (SD) for continuous variables.Data analysis was conducted using Stata/MP Version 16 (Stata Corp. LP, USA/ METAN package).

Results
After excluding duplicates (n = 244) and ineligible items from the 879 publications identified in the initial search, 133 case reports/case series met our eligibility criteria.All included studies had a quality score greater than 7/10 (Supplementary Table 1).
The median (IQR) age was 50 [38,63] years, ranging from 14 to 84 years, and 25 (62.5%)patients were male.Regarding vaccine type, 70% of cases (n = 28) received mRNA-based vaccines.While in most of the patients with vector vaccine-associated PTS, the symptoms appeared on the first dose of the vaccine (10/12), such a pattern was not observed in mRNA vaccine-related PTS (First/Second doses (n): 14/14).
Regarding medications, 10 (56%) patients were treated with corticosteroids alone, 6 (33%) with both corticosteroids and a viral agent.Corticosteroids were combined with Fluorometholone eye drops in one case and with a topical antibiotic in another patient.At the follow-up, the symptoms had resolved in all patients without any complications.

Small fiber neuropathy
We included three articles (two case reports [128,129] and one case series [130]) reporting five COVID-19-associated small fiber neuropathy (SFN) in our study (Table 1, Supplementary Table 7).These patients were reported from Austria (n = 3) and the USA (n = 2).All five patients were female, aged between 32 and 64, and had received mRNA vaccines (Pfizer and Spikevax).In 4 out of 5 patients, symptoms appeared after receiving the second dose.

Tolosa-hunt syndrome
One Tolosa-Hunt patient from the USA was included in our study [131] (Supplementary Table 7).The patient was a 45-year-old male who received a vector-based vaccine.The patient presented with left-sided headache, periorbital pain, ptosis, and decreased visual acuity.The brain CT indicated a sinus thrombosis, while the brain MRI reported a perineural enhancement surrounding the optic nerve sheath.The patient underwent steroid treatment, and the symptoms improved in 2 months.
Repetitive nerve stimulation (RNS) was positive in 13 out of 15, and Single fiber electromyography (SFEMG) in all 4 patients who received the test.Acetylcholine receptor (AChR) antibody was positive in 16 out of 20 patients and Muscle-specific kinase (MuSK) negative in all 4 tested patients.Complete improvement at discharge/1month follow-up was reported in 79% (11/14), a myasthenic crisis in 14% (2/14), and unchanged symptoms at 3 months in 7% (1/14) of the cases.

Discussion
Based on our comprehensive literature review, a total of 171 GBS, 40 PTS, 22 MG, 19 FNP, 5 SFN, and 1 Tolosa-Hunt syndrome cases following COVID-19 vaccination have been reported so far across the world.Overall, reported cases were mainly adults; FNP patients (median age: 38 years) were the youngest, and MG patients (64 years) were the oldest group.While all SNF and most FNP cases were female, in other groups, the male gender was predominant.The median time from vaccine to symptom was less than 2 weeks in all groups, ranging from 3 days in FNP patients to 13 days in GBS cases.Symptoms mainly appeared following the first dose of vector-based vaccine, but there was no specific pattern for mRNA-based associated NMD.While most reported cases experienced a benign course of the disease, death occurred in 3 out of 123 GBS patients, and 2 out of 14 MG patients developed a myasthenic crisis.
The occurrence of NMD has been reported following influenza and other vaccines [133,[144][145][146][147][148].A pooled analysis of GBS following mass immunizations with Influenza, Human papillomavirus, and Measles-Rubella vaccines, including 58 studies (2,110,441,600 participants), revealed an incidence rate of 3.09 per million in 6 weeks of vaccination, without a sex difference.Contrary to GBS induced by COVID-19 vaccines, most GBS cases associated with other vaccines were younger than 18 or older than 60 years old; their different target population could  [149].A little more than half of the patients were female (55.7%), and only 2.2% had a prior FNP history.A similar gender pattern was observed in FNP following COVID-19 vaccines.However, a prior history of FNP was reported in 21% of patients.Also, a total of 42 definite incident cases of MG occurred following Influenza and Hepatitis B vaccines in American adults between 1990 and 2017 [150]; these cases had a higher mean (SD) time from vaccine to symptoms compared to MG cases associated with COVID-19 vaccines (10 (10.7) vs 7.1(6.6),respectively).Overall, MG is mainly diagnosed between 10 and 70 years old [23,24], and affected female patients are younger than their male counterparts (mean age: 28 vs. 42 years, respectively) [25].Gender ratio differs by MG type; contrary to pure ocular or bulbar MG, cases with generalized MG are predominantly female (female/male ratio: 3:2 or higher) [26].Less than 40% of MG cases following other vaccines were older than 60 years (Mean age (SD): 49.0 (18.9) years, Range: 18 to 84 years), without a gender predominance [22].However, COVID-19 vaccine-associated MG cases were predominantly male, overall, and by MG type, and half of them were aged 70 years or older (Mean age (SD): 61.0 (19.3) years).
In this study, we summarized data on COVID-19 vaccine-associated NMD provided by case reports/series.The exact mechanism by which vaccines could induce neuromuscular diseases remains unknown.However, the immunization processes following the vaccines could provoke an autoimmune response by establishing an inflammatory environment.If vaccine antigens mimic self-antigens, the immune response could crossreact with self-antigens, leading to an autoimmune reaction (Molecular mimicry mechanism).Furthermore, during immune responses to vaccine antigens, inflammatory signals can activate self-reactive T cells involved in the autoimmune processes (Bystander effect mechanism).Also, the activation of self-reactive T cells could be triggered via self-antigens released upon selftissue damage following inflammatory cascade (Epitope spreading mechanism).Vaccines containing dsRNA or its analogs can also overexpress IFN-b, a key factor in thymic events leading to MG [3].
The temporal association of neuromuscular disorders and COVID-19 vaccination cannot easily be translated into a causal relationship, and the evidence in this regard is inadequate [151].Thus, further studies are required to clarify this association.
SFN is categorized as primary and secondary to vaccination or diseases such as kidney failure, diabetes, infections, or autoimmune.As Finsterer et al.129 noted, the clinical presentation of COVID-19 vaccineassociated SFN is similar to other secondary SFNs.Also, evidence on the beneficial effects of IVIG supports the autoimmune nature of the SFN associated with COVID-19 vaccines.
The median time from vaccine to symptom was less than 2 weeks in all NMD, mainly after the first dose; a case can be made that vaccination may have exacerbated an already existing but asymptomatic form in the vaccinated individuals instead of triggering a new onset of the disease.

Limitation and strengths
This review acknowledges certain limitations inherent in our study design.Firstly, due to the nature of the collected data, We couldn't analyze the link between the number of COVID-19 vaccine doses and neuromuscular disorders.Furthermore, we couldn't assess the effects of mixing different COVID-19 vaccines for primary and booster doses.Our study can't conclusively establish a causal relationship between COVID-19 vaccination and neuromuscular events.Few cases of neuromuscular disorders like Tolosa-Hunt syndrome and SFN were reported.
Furthermore, our pooled data sets were incomplete for some variables, such as laboratory tests or imaging.However, we pooled data from all reported cases of NMD following COVID-19 vaccines using a comprehensive search strategy to provide a better understanding of this issue.To our knowledge, this is the first systematic review of reported cases of COVID-19 vaccine-associated NMD.

Conclusion
Based on our comprehensive literature review, COVID-19 vaccines might induce some neuromuscular diseases.These cases mainly occurred after administering the most frequently used COVID-19 vaccines.The age distribution and gender characteristics of affected patients may differ based on the NMD type.About two-thirds of the cases occurred in less than 2 weeks after vaccination.Most cases developed the symptoms following the first dose of vector-based vaccines.The majority of these patients experienced a benign disease course.

Fig. 1
Fig. 1 PRISMA flow chart of the eligible study selection

Table 1
Characteristics, findings, treatments, and clinical outcome of reported polyneuropathy cases

Table 1
(continued) AIDP Acute inflammatory demyelinating polyneuropathy, AMAN Acute motor axonal neuropathy, AMSAN Acute motor and sensory axonal neuropathy, BFP Bilateral facial palsy, CT Computed Tomography, EMG Electromyography, F Female, FDFN Focal demyelination of facial nerves, FW Facial Weakness, GABA Gamma-Aminobutyric Acid, IM Intramuscular, IQR Interquartile range, IVIG Intravenous Immunoglobulin, J&J Johnson and Johnsons, MRI Magnetic Resonance Imaging, M Male, MFS Miller fisher syndrome, mRNA messenger Ribonucleic Acid, NCS Nerve conduction study, NR Not reported, NSAID Non-steroidal anti-inflammatory drug, PLEX Plasma Exchange, SM Sensory motor a Pfizer or Spikevax, b AstraZeneca, Covaxin, Sputnik V, or Johnson and Johnson

Table 2
Characteristics, findings, treatments, and clinical outcome of reported Myasthenia gravis cases AChR Acetylcholine Receptor antibody, CT Computed Tomography, EMG Electromyography, IM Intramuscular, IQR Interquartile range, IVIG Intravenous Immunoglobulin, MRI Magnetic Resonance Imaging, mRNA messenger Ribonucleic Acid, MuSK Muscle Specific Kinase antibody, PLEX Plasma Exchange, Pred Prednisolone, Pyr pyridostigmine, RNS Repetitive Nerve Stimulation, SFEMG Single Fiber Electromyography a Pfizer or Spikevax, b AstraZeneca, c all bilateral except patient #18, who had left-sided ptosis